Marine-Derived Bioactive Peptides with Pharmacological Activities- A Review

Some nutritional factors are related to chronic disease. In response to increased concern regarding nutrition and health, the functional and nutraceuticals food markets have been developed. During food digestion, proteins are hydrolyzed and a wide range of peptides are formed. Some of these peptides have special structures which permit them to confer particular biological functions. Marine animals which involve more than half of the world biological varieties are a wide source of bioactive proteins and peptides. Marine derived peptides show various physiologic functions such as anti-oxidant, antimicrobial, anti-cancer, Angiotensin-1-Converting Enzyme (ACE) glucosidase and α-amylase inhibitory effects in vitro. Before application of marine bioactive peptides as nutraceuticals or functional food ingredients, their efficacy should be approved through pre-clinical animal and then clinical studies. The aim of this study was to review the studies conducted on the pharmacological effect of marine bioactive peptides in animal models and humans.

Recent studies have shown a relation between nutritional factors and prevalence of some chronic disease [1]. In response to increased concern regarding nutrition and health, the functional food markets have been developed. The functional foods are those which provide body nutritional needs and also have health properties by regulating one or more physiological functions [2]. The world trade of functional foods has increased 6 percent in 5 recent years, and it is estimated to reach up to 54 billion dollars [3].

Marine animals that comprise about half of the world’s biodiversity provided a wide spectrum of bioactive compounds which can be used in the production of functional foods [4]. Marine biologically active compounds include bioactive peptides, oligosaccharides, omega fatty acids, enzymes, minerals, pigments and bio-polymers [5].

Proteins are of most prominent nutritional compounds and excellent source of all essential amino acids. They are responsible for building, maintaining and repairing of body tissue and are one of the main energy sources. In addition, proteins in food affect sensory (texture, colour, taste and odour) and physico-chemical (solubility, viscosity, gel formation and emulsifying) [2]. Furthermore, some of proteins in nutritional regimens have biologic properties and improve the health of consumers. In this regard, it has been reported that fish protein can lower blood pressure and lipid and therefore decrease the risk of atherosclerosis and heart disease [3].

During food digestion, proteins are hydrolyzed and a wide range of peptides are formed. Some of these peptides have special structures which permit them to confer particular biological functions. These peptides have 2-20 amino acids and are released during hydrolysis process [6]. The released form of these peptides exhibits various physiologic functions such as immune stimulatory [7], anti-cancer [8], antimicrobial [9], anti-oxidant [10] and blood pressure, glucose and lipid lowering [6] activities due to their bioactive features.

Bioactive peptides are proteins synthesized in the cell in the form of large prepropeptides which are then cleaved and modified to give active products. They are obtained mainly from herbal and animal sources. Animal sources of bioactive peptides include milk, egg, red meat and marine animals [2]. Marine animals which involve more than half of the world biodiversity are a wide source of bioactive proteins and peptides [11]. There are increasing evidences that numerous peptides and protein hydrolysates derived from marine animals including fish, mollusks, crustaceans and fishery wastes (substandard meat, head, viscera, skin, fins and skeletons) can improve human health and prevent chronic diseases [2].

In general, bioactive peptides are obtained from whole protein molecules through enzymatic hydrolysis and fermentation. Digestion of protein by proteolytic enzymes and microbes during fermentation may increase their nutritional and pharmaceutical function [12]. Enzymatic hydrolysis is one of the most common methods used for the production of bioactive peptides. Enzymatic hydrolysis is carried out by employing autolytic process or commercial protease [13]. Various commercial proteases from plants, animals and microbial sources such as trypsin, chymotrypsin, pepsin, alcalase, papain, pronase and collagenase are used for the production of bioactive peptides. In addition, autolysis process by digestive or autolytic enzymes of animal can also be used for the production of bioactive compounds [14].

Until today, numerous studies have assessed the therapeutic properties of marine bioactive peptides in vitro and few studies have been performed over animal model or human [2]. The aim of the present study was an overview on the results of previous studies regarding therapeutic effects of marine bioactive peptides.

High blood pressure affects approximately 25% of adults today and is estimated to progress to 29% by 2025, a population of 1.56 billion [15]. The high blood pressure is associated with some cardiovascular diseases such as atherosclerosis, myocardial infarction and stroke. The ACE plays a critical role in the regulation of hypertension. The synthetic inhibitors of ACE enzyme can lead to different side effects [16]. A number of clinical trials have previously reported that consumption of some proteins in diet can lower blood pressure [2]. The effects of ACE inhibition by some marine peptides have been shown in vitro and those with the most level of inhibitory properties have been isolated and sequenced by chromatography methods [14,17,18]. The effects of purified peptides were also investigated in several studies. For example a single oral administration (10mg/kg of body weight) of the purified peptides isolated from fermented blue mussel [14], yellow fin sole frame [17] and izumi shrimp muscle [19] have been reported to reduce systolic blood pressure in spontaneously hypertensive rats. Long-term oral administration of jellyfish collagen peptides has also shown antihypertensive activity in renovascular hypertensive rats [20].

Hyperlipidemia and hypercholesterolemia have an important role in the occurrence of atherosclerosis, coronary artery disease, ischemic heart disease and peripheral vascular disease [21]. Epidemiological studies show that Greenland Eskimos and Japanese fishermen who eat more fish appear to have a lower rate of heart disease [22]. Possible roles of fish protein in reducing the risk of cardiovascular diseases might be related to their hypolipidemic and hypocholesterolemic activities [5]. The evidence has suggested that protein hydrolysate derived from soybean [23] and fish [24] show better anti-hyperlipidemic effect than non-hydrolyzed proteins. Hypolipidemic and hypocholesterolemic activity of protein hydrolysate derived from muscle of bogue [24], sardine [25], Alaska pollock [26,27] and zebra blenny [28] have been shown in rat fed on high cholesterol and high fat diet. They reduce atherosclerotic development through several mechanisms including reduction of serum lipid such as Total cholesterol, Triglycerides and low-density lipoprotein (TG, TC, and LDL), reduction of serum Malondialdheyde (MDA), and increase activities of antioxidant enzymes.

The prevalence of diabetes is increasing promptly worldwide and more than 194 million people have been afflicted. It has been estimated that the number of patients reach to 335 million in 2025. Of diabetes types, the type 2 diabetes is highly prevalent and involves 90% of cases [29]. Although some drugs, dietary patterns and exercise program have improved hyperglycaemia due to diabetes, these programs cannot efficiently inhibit and prevent its complications. Therefore, discovery and development of new drugs has crucial importance [30]. As exhibited in [Table/Fig-1] [14,17,19,20,24-28,30-33], some peptides and hydrolysis proteins from marine sources are also able to heal hyperglycaemia, oxidative stress and liver and kidney damage induced by diabetes in animal models and human. It is reported that the administration of protein hydrolysates from zebra blenny muscle has hypoglycemic and hypolipidemic effects in alloxan-induced diabetic rats. It also shows potent hepatoprotective against alloxan induced hepatic damage [30]. Protein hydrolysates obtained from goby fish muscles have also been shown to display ameliorating effects on hyperglycaemia, oxidative stress and nephrotoxicity in rats fed on high-fat-high-fructose diet [31]. Clinical research shows that taking oral MCPs provides protection against hyperglycaemia, hypertension and dyslipidemia in type 2 diabetic patients [32,33]. These effects might be related to the regulation of the level of molecules involved in diabetic and hypertensive pathogenesis such as hs-CRP, nitric oxide, bradykinin, PGI2 and adiponectin [32,33].

The skin is the largest organ of the body which protects it from damaging agents. The collagen involves 30% of total body and 70% of skin proteins. There are more than 20 recognized collagen types which classified in three main groups. Type 1 collagen which is the predominant collagen in the body, has an important role in maintenance of skin integrity [34]. Skin ageing is accompanied by significant decrease in type 1 collagen [35]. Previous studies have shown that consumption of collagen peptides have positive effects on hair thickening, improvement of nail disorders, increasing size of collagen fibrils, increasing density of fibroblasts and formation of collagen fibrils in the dermis [34]. Marine by products contain 30% collagen which is a potential source for production of collagen peptides [36]. Skin protection and wound healing activities of collagen peptides derived from marine resources are exhibited in [Table/Fig-2] [36-38]. Collagen peptides prepared from chum salmon skin have been reported to exhibit wound healing [36] and skin protection properties [37]. In a single-blind case-control clinical study, 2-month oral intake of marine collagen peptides remarkably improved skin elasticity, sebum production and dermal ultrasonic markers in healthy volunteers [38].

Uncontrolled and inappropriate use of antibiotics has resulted in the emergence of new complicated and opportunistic pathogens resistant to commonly used antibiotics. So, researchers are interested in controlling these agents not only by discovering new antimicrobials and antibiotic therapy but also by discovering new antimicrobial compounds having immunomodulatory effect [39].

It has been reported that peptides from enzymatic hydrolysis of herbal (fermented rice) [39] and animal (casein in milk and egg albumin) [40,41] proteins have immunomodulatory effects. Marine animal are another important source of bioactive peptides with numerous immunomodulatory activities. Several studies regarding the immunomodulatory effects of marine bioactive peptides in animal models and human are shown in [Table/Fig-3] [3,7,42,43]. Oyster hydrolysate was observed to inhibit the growth of transplantable sarcoma-S180 in mice by approximately 40%. Also, the immunomodulatory effects in S180-bearing mice were reported. Oyster hydrolysate is supposed to show immunomodulatory effects through interaction with Natural Killer (NK) cells, lymphocyte and macrophage [7]. Oligo-peptides produced by enzymatic hydrolysis of chum salmon have been shown to have immune-stimulatory properties on UV-induced immune suppression in mice. Mice fed with oligo-peptides showed significant increase in lymphocyte proliferation, number of plaque-forming cells, activity of natural killer, Th1 and CD4 cells [42]. Commercial peptide derived from shark protein has also been shown to stimulate immune response in healthy volunteers [3].

The decreased function of brain due to human ageing can lead to cognitive disorders such as memory impairment and amnesia. In 21^st century, the global population goes toward ageing which is accompanied by related diseases such as Alzheimer’s and Parkinson [44]. Oxidative stress is an important risk factor in the development of age-related memory and learning deficits. High generation of reactive oxygen species in conjunction with the weakened antioxidant defense system can lead to neuronal damage and eventually neurological disorders [45]. Today, various antioxidants are widely in use to prevent and treat some of these conditions [44-46].

There are few and limited studies on the protective effects of marine bioactive peptides on memory and learning deficits [Table/Fig-4] [47-49]. Marine Collagen Peptide (MCP) isolated from chum salmon was shown to ameliorate age-related cognitive deficits in C57BL/6J mice [47]. It also reported to increase life span and inhibit development of spontaneous tumours in Sprague-Dawley rats [48]. The protective effects of MCP on age-related neurodegeneration are related to the inhibition of oxidative stress and apoptosis in neuronal cells. It also promotes expression of neurogenesis Brain-Derived Factor (BDNF) in the hippocampi of aged rats [47,48].

In recent years, lifestyle modification has led to appearance of new health problems such as overweight and obesity. Overweight and obesity are known to increase the risk of several chronic diseases including coronary heart disease, type 2 diabetes mellitus, hypertension, stroke and some type of cancers [50]. Body weight is regulated by some endocrine hormones such as insulin and leptin. In addition, short messaging peptides, such as cholecystokinin, glucagon-like Ptyd -1 (GLP-1) and ghrelin are also involved in appetite and weight control [51]. Among various food compounds, proteins and their hydrolysate can stimulate the secretion of CCK and GLP-1 [52]. A summary of studies on the anti-obesity and anti-appetite effects of marine peptides are presented in [Table/Fig-5] [53-56]. The elevated plasma bile acids with saithe protein hydrolysate, rich in taurine and glycine, intake was observed in rats but soy protein or casein intake did not caused such effect. It is reported that conjugation of bile acids to taurine or glycine promotes their solubility and increases liver bile acids secretion. These muscle derived peptides were shown to reduce liver and visceral lipids and up regulate the expression of genes involved in fatty acid oxidation and energy production [53]. Low molecular weight peptides from smooth hound and blue whiting muscle protein have been shown to reduce food intake and appetite in rats [54,55]. These peptides were shown to stimulate the release of satiety hormones such as Cholecystokinin (CCK) and glucagon-like peptide-1 (1-GLP) from the gastrointestinal tract [54]. Protein hydrolysate derived from blue whiting muscle also shows weight loss benefits in overweight women [56].

Until now, therapeutic effects of marine bioactive peptides have been studied in vitro and in cell culture, but there are fewer studies in animal models [2]. The present study was an overview on therapeutic effects of bioactive peptides in animal models and human. As summarized in [Table/Fig-1,2,3,4 and 5], the positive effects of marine bioactive peptides in animal model include immune stimulation, blood pressure, lipids and glucose lowering, anti-obesity and satiety enhancing, skin protection and wound healing as well as memory and learning enhancing properties. In addition, the effects of marine bioactive peptides in protecting the liver against alcohol injury [57], development of long bone [58] and anti-oxidative stress [59] have been reported in animal models. According to tables, anti-obesity and satiating effects of protein hydrolysate from blue whiting muscle [32] and antihypertensive, antidiabetic and skin protection activities of marine collagen peptides [33,38] have been shown in human trials.

Before introducing bioactive peptides into market or their consumption as food components, there is a need to approve their therapeutic features in human studies and to take legal permits from the relevant authorities Food For Specified Health Uses (FOSHU), Food and Drug Administration (FDA), and European Food Safety Authority (EFSA) [13].

A number of peptides and proteins hydrolyzed derived from marine resources are sold with different brand names around the world. Some of these products have been shown to exhibit pharmacological activities in animal model and human. Human trials have shown that peptides in Valtyron^® have antihypertensive effects in hypertensive subjects [18]. The immunomodulatory effects of two natural products such as PeptiBal™ [3] and Seacure [43] were also observed in healthy volunteers. Ziconotide is a natural peptide obtained from cone snail which shows analgesic activity in subjects with chronic pain [60]. Ziconotide and Valtyron^® have recently been passed as safe by the EFSA and FDA [60].

Each year, both onboard and on-shore marine processing plants generate large amount of waste including substandard muscles, viscera, heads, skins, fins, frames and shell waste. Furthermore, large quantities of fish, molluscs and crustaceans are discarded due to small size or low consumer preference. It is estimated that about 64 million tons of low-value marine animals and by-products is discarded each year and most of them are used as fertilizer and animal feed [11]. This waste could be utilized as valuable sources for the production of bioactive peptides which lead to better exploitation of marine resources [2].

In general, substrate protein, type of enzymes and hydrolysis time and conditions (like temperature and pH) can affect structure and molecular weight of peptides and therefore their biological activities [13]. In order to produce peptides with certain molecular weight and specific activity, peptides are isolated and purified using ultrafiltration and chromatographic methods. The sequences of purified peptide are determined using mass spectrometry [59]. The sequenced peptides can be synthesized to evaluate their biological activities in animal models and human. Production of protein hydrolysis from marine animals or by-product is economically affordable and cost-effective, but production of peptides with specific sequences in commercial scale is limited due to high cost of peptides synthesis [13].

Marine bioactive peptides produced from different sources of protein through enzymatic hydrolysis or fermentation have been demonstrated to possess diverse physiological functions such as immune stimulation, blood pressure and lipids lowering, anti-diabetic, anti-obesity, skin protection and wound healing activities as well as memory and learning enhancing property in animal model or in human. Marine bioactive peptides seem to have a potential as a functional ingredient in food product or nutraceuticals to increase consumer health and wellbeing.

[1]. Who J, Consultation FE, Diet, nutrition and the prevention of chronic diseases World Health Organ Tech Rep Ser 2003 916(5):312-23.  [Google Scholar]

[2]. Harnedy PA, FitzGerald RJ, Bioactive peptides from marine processing waste and shellfish: A review J Funct Foods 2012 4(1):6-24.  [Google Scholar]

[3]. Boutin Y, Paradis M-E, Couture P, Lamarche B, Immunological effect of fish protein supplementation on healthy adults J Nat Prod 2012 5:37-44.  [Google Scholar]

[4]. Sable R, Parajuli P, Jois S, Peptides, peptidomimetics, and polypeptides from marine is: a wealth of natural is for pharmaceutical applications Mar Drugs 2017 15(4):124-39.  [Google Scholar]

[5]. Kromhout D, Bosschieter EB, Coulander CdL, The inverse relation between fish consumption and 20-year mortality from coronary heart disease NEngl J Med 1985 312(19):1205-09.  [Google Scholar]

[6]. Pangestuti R, Kim S-K, Bioactive peptide of marine origin for the prevention and treatment of non-communicable diseases Mar Drugs 2017 15(3):6774  [Google Scholar]

[7]. Wang Y-K, He H-L, Wang G-F, Wu H, Zhou B-C, Chen X-L, Oyster (Crassostrea gigas) hydrolysates produced on a plant scale have antitumour activity and immunostimulating effects in BALB/c mice Marine Drugs 2010 8(2):255-68.  [Google Scholar]

[8]. Picot L, Bordenave S, Didelot S, Fruitier-Arnaudin I, Sannier F, Thorkelsson G, Antiproliferative activity of fish protein hydrolysates on human breast cancer cell lines Process Biochem 2006 41(5):1217-22.  [Google Scholar]

[9]. Najafian L, Babji AS, A review of fish-derived antioxidant and antimicrobial peptides: their production, assessment, and applications Peptides 2012 33(1):178-85.  [Google Scholar]

[10]. Nikoo M, Mac Regenstein J, Ghomi MR, Benjakul S, Yang N, Xu X, Study of the combined effects of a gelatin-derived cryoprotective peptide and a non-peptide antioxidant in a fish mince model system LWT Food Sci Technol 2015 60(1):358-64.  [Google Scholar]

[11]. Nikoo M, Xu X, Benjakul S, Xu G, Ramirez-Suarez JC, Ehsani A, Characterization of gelatin from the skin of farmed Amur sturgeon Acipenser schrenckii Int Aquat Res 2011 3(1):135-45.  [Google Scholar]

[12]. Beddows CG, Fermented fish and fish products Microbiol Ferment Foods 1998 55(2):416-40.  [Google Scholar]

[13]. Nikoo M, Benjakul S, Ehsani A, Li J, Wu F, Yang N, Antioxidant and cryoprotective effects of a tetrapeptide isolated from Amur sturgeon skin gelatin J Funct Foods 2014 7:609-20.  [Google Scholar]

[14]. Je J-Y, Park P-J, Byun H-G, Jung W-K, Kim S-K, Angiotensin I converting enzyme (ACE) inhibitory peptide derived from the sauce of fermented blue mussel, Mytilus edulis Bioresour Technol 2005 96(14):1624-29.  [Google Scholar]

[15]. Coresh J, Wei GL, McQuillan G, Brancati FL, Levey AS, Jones C, Prevalence of high blood pressure and elevated serum creatinine level in the United States: findings from the third National Health and Nutrition Examination Survey (1988-1994) Arch Intern Med 2001 161(9):1207-16.  [Google Scholar]

[16]. Menezes IA, Barreto C, Antoniolli ÂR, Santos MR, Sousa DPd, Hypotensive activity of terpenes found in essential oils Z Naturforsch C Bio Sci 2010 65(9-10):562-66.  [Google Scholar]

[17]. Jung W-K, Mendis E, Je J-Y, Park P-J, Son BW, Kim HC, Angiotensin I-converting enzyme inhibitory peptide from yellowfin sole (Limanda aspera) frame protein and its antihypertensive effect in spontaneously hypertensive rats Food Chem 2006 94(1):26-32.  [Google Scholar]

[18]. Kawasaki T, Seki E, Osajima K, Yoshida M, Asada K, Matsui T, Antihypertensive effect of valyl-tyrosine, a short chain peptide derived from sardine muscle hydrolyzate, on mild hypertensive subjects J Hum Hypertens 2000 14(8):519  [Google Scholar]

[19]. Nii Y, Fukuta K, Yoshimoto R, Sakai K, Ogawa T, Determination of antihypertensive peptides from an izumi shrimp hydrolysate Biosci Biotechnol Biochem 2008 72(3):861-64.  [Google Scholar]

[20]. Zhuang Y, Sun L, Zhang Y, Liu G, Antihypertensive effect of long-term oral administration of jellyfish (Rhopilema esculentum) collagen peptides on renovascular hypertension Mar Drugs 2012 10(2):417-26.  [Google Scholar]

[21]. Bates HM, Prevalence of hyperlipidemia in a large sample population J Cardiovasc Pharmacol 1982 4(3):201-07.  [Google Scholar]

[22]. Kromhout D, n-3 fatty acids and coronary heart disease: epidemiology from Eskimos to Western populations J Intern Med 1989 225(S731):47-51.  [Google Scholar]

[23]. Sugano M, Goto S, Yamada Y, Yoshida K, Hashimoto Y, Matsuo T, Cholesterol-lowering activity of various undigested fractions of soybean protein in rats J Nutr 1990 120(9):977-85.  [Google Scholar]

[24]. Lassoued I, Trigui M, Ghlissi Z, Nasri R, Jamoussi K, Kessis M, Evaluation of hypocholesterolemic effect and antioxidant activity of Boops boops proteins in cholesterol-fed rats Food Funct 2014 5(6):1224-31.  [Google Scholar]

[25]. Athmani N, Dehiba F, Allaoui A, Barkia A, Bougatef A, Lamri-Senhadji MY, Sardina pilchardus and Sardinella aurita protein hydrolysates reduce cholesterolemia and oxidative stress in rat fed high cholesterol diet J Exp Integr Med 2015 5(1):47-53.  [Google Scholar]

[26]. Hosomi R, Fukao M, Fukunaga K, Okuno M, Yagita R, Kanda S, Effect of fish protein and peptides on lipid absorption in rats Trace Nutr Res 2010 27(6):21-27.  [Google Scholar]

[27]. Hosomi R, Fukunaga K, Arai H, Kanda S, Nishiyama T, Yoshida M, Fish protein hydrolysates affect cholesterol metabolism in rats fed non-cholesterol and high-cholesterol diets J Med Food 2012 15(3):299-306.  [Google Scholar]

[28]. Ktari N, Belguith-Hadriche O, Amara IB, Hadj AB, Turki M, Makni-Ayedi F, Cholesterol regulatory effects and antioxidant activities of protein hydrolysates from zebra blenny (Salaria basilisca) in cholesterol-fed rats Food Funct 2015 6(7):2273-82.  [Google Scholar]

[29]. Shaw JE, Sicree RA, Zimmet PZ, Global estimates of the prevalence of diabetes for 2010 and 2030 Diabetes Res Clin Pract 2010 87(1):4-14.  [Google Scholar]

[30]. Ktari N, Mnafgui K, Nasri R, Hamden K, Bkhairia I, Hadj AB, Hypoglycemic and hypolipidemic effects of protein hydrolysates from zebra blenny (Salaria basilisca) in alloxan-induced diabetic rats Food Funct 2013 4(11):1691-99.  [Google Scholar]

[31]. Nasri R, Abdelhedi O, Jemil I, Daoued I, Hamden K, Kallel C, Ameliorating effects of goby fish protein hydrolysates on high-fat-high-fructose diet-induced hyperglycaemia, oxidative stress and deterioration of kidney function in rats Chem Biol Interact 2015 242:71-80.  [Google Scholar]

[32]. Cui-Feng Z, Guan-Zhi L, Hong-Bin P, Zhang F, Yun C, Yong L, Effect of marine collagen peptides on markers of metabolic nuclear receptors in type 2 diabetic patients with/without hypertension Biomed Environ Sci 2010 23(2):113-20.  [Google Scholar]

[33]. Zhu C-F, Li G-Z, Peng H-B, Zhang F, Chen Y, Li Y, Treatment with marine collagen peptides modulates glucose and lipid metabolism in Chinese patients with type 2 diabetes mellitus Appl Physiol Nut Metabol 2010 35(6):797-804.  [Google Scholar]

[34]. Tanaka M, Koyama Y-i, Nomura Y, Effects of collagen peptide ingestion on UV-B-induced skin damage Biosci Biotechnol Biochem 2009 73(4):930-32.  [Google Scholar]

[35]. Matsuda N, Koyama Y-i, Hosaka Y, Ueda H, Watanabe T, Araya T, Effects of ingestion of collagen peptide on collagen fibrils and glycosaminoglycans in the dermis JNutr Sci Vitaminol 2006 52(3):211-15.  [Google Scholar]

[36]. Zhang Z, Wang J, Ding Y, Dai X, Li Y, Oral administration of marine collagen peptides from Chum Salmon skin enhances cutaneous wound healing and angiogenesis in rats J Sci Food Agr 2011 91(12):2173-79.  [Google Scholar]

[37]. Wang J, Xu M, Liang R, Zhao M, Zhang Z, Li Y, Oral administration of marine collagen peptides prepared from chum salmon (Oncorhynchus keta) improves wound healing following cesarean section in rats Food Nutr Res 2015 59(1):33-39.  [Google Scholar]

[38]. De Luca C, Mikhal’chik EV, Suprun MV, Papacharalambous M, Truhanov AI, Korkina LG, Skin antiageing and systemic redox effects of supplementation with marine collagen peptides and plant-derived antioxidants: A single-blind case-control clinical study Oxid Med Cell Longev 2016 3(1):22-29.  [Google Scholar]

[39]. Koh J, Yu K, Suh H, Biological activities of Saccharomyces cerevisiae and fermented rice bran as feed additives Lett Appl Microbiol 2002 35(1):47-51.  [Google Scholar]

[40]. Mhan-Pyo Y, Hye-Yun E, Ki-Jeong N, Araki S, Moshira E-A, Motobu M, Enhanced phagocytic activity of neutrophils caused by administration of egg white derivatives (EWD) in cats injected with cyclophosphamide (CPA) J Vet Med Sci 2001 63(3):269-74.  [Google Scholar]

[41]. Matar C, Valdez Jc, Medina M, Rachid M, Perdigon G, Immunomodulating effects of milks fermented by Lactobacillus helveticus and its non-proteolytic variant J Dairy Res 2001 68(04):601-09.  [Google Scholar]

[42]. Yang R, Pei X, Wang J, Zhang Z, Zhao H, Li Q, Protective effect of a marine oligopeptide preparation from Chum Salmon (Oncorhynchus keta) on radiation-induced immune suppression in mice J Sci Food Agr 2010 90(13):2241-48.  [Google Scholar]

[43]. Duarte J, Vinderola G, Ritz B, Perdigón G, Matar C, Immunomodulating capacity of commercial fish protein hydrolysate for diet supplementation Immunobiol 2006 211(5):341-50.  [Google Scholar]

[44]. Rabiei Z, Rafieian-Kopaei M, Mokhtari S, Alibabaei Z, Shahrani M, The effect of pretreatment with different doses of Lavandula officinalis ethanolic extract on memory, learning and nociception Biomed Aging Pathol 2014 4(1):71-76.  [Google Scholar]

[45]. Rabiei Z, Rafieian-kopaei M, Heidarian E, Saghaei E, Mokhtari S, Effects of Zizyphus jujube extract on memory and learning impairment induced by bilateral electric lesions of the nucleus Basalis of Meynert in rat Neurochem Res 2014 39(2):353-60.  [Google Scholar]

[46]. Rabiei Z, Hojjati M, Rafieian-Kopaeia M, Alibabaei Z, Effect of Cyperus rotundus tubers ethanolic extract on learning and memory in animal model of Alzheimer Biomed Aging Pathol 2013 3(4):185-91.  [Google Scholar]

[47]. Pei X, Yang R, Zhang Z, Gao L, Wang J, Xu Y, Marine collagen peptide isolated from Chum Salmon (Oncorhynchus keta) skin facilitates learning and memory in aged C57BL/6J mice Food Chem 2010 118(2):333-40.  [Google Scholar]

[48]. Liang J, Pei X-R, Wang N, Zhang Z-F, Wang J-B, Li Y, Marine collagen peptides prepared from chum salmon (Oncorhynchus keta) skin extend the life span and inhibit spontaneous tumour incidence in sprague-dawley rats J Med Food 2010 13(4):757-70.  [Google Scholar]

[49]. Hama A, Sagen J, Antinociceptive effects of the marine snail peptides conantokin-G and conotoxin MVIIA alone and in combination in rat models of pain Neuropharmacol 2009 56(2):556-63.  [Google Scholar]

[50]. Flegal KM, Graubard BI, Williamson DF, Gail MH, Cause-specific excess deaths associated with underweight, overweight, and obesity JAMA 2007 298(17):2028-37.  [Google Scholar]

[51]. Ranganath L, Beety J, Morgan L, Wright J, Howland R, Marks V, Attenuated GLP-1 secretion in obesity: cause or consequence? Gut 1996 38(6):916-19.  [Google Scholar]

[52]. Geraedts MC, Troost FJ, Fischer MA, Edens L, Saris WH, Direct induction of CCK and GLP-1 release from murine endocrine cells by intact dietary proteins Mol Nutr Food Res 2011 55(3):476-84.  [Google Scholar]

[53]. Liaset B, Madsen L, Hao Q, Criales G, Mellgren G, Marschall H-U, Fish protein hydrolysate elevates plasma bile acids and reduces visceral adipose tissue mass in rats BBA- Mol Cell Biol Lipid 2009 1791(4):254-62.  [Google Scholar]

[54]. Bougatef A, Ravallec R, Nedjar-Arroume N, Barkia A, Guillochon D, Nasri M, Evidence of in vivo satietogen effect and control of food intake of smooth hound (Mustelus mustelus) muscle protein hydrolysate in rats J Funct Food 2010 2(1):10-16.  [Google Scholar]

[55]. Cudennec B, Fouchereau-Peron M, Ferry F, Duclos E, Ravallec R, In vitro and in vivo evidence for a satiating effect of fish protein hydrolysate obtained from blue whiting (Micromesistius poutassou) muscle JFunct Food 2012 4(1):271-77.  [Google Scholar]

[56]. Zaïr Y, Duclos E, Housez B, Vergara C, Cazaubiel M, Soisson F, Evaluation of the satiating properties of a fish protein hydrolysate among overweight women: a pilot study Nutr Food Sci 2014 44(5):389-99.  [Google Scholar]

[57]. Lin B, Zhang F, Yu Y, Jiang Q, Zhang Z, Wang J, Marine collagen peptides protect against early alcoholic liver injury in rats Br J Nutr 2012 107(08):1160-66.  [Google Scholar]

[58]. Xu Y, Han X, Li Y, Effect of marine collagen peptides on long bone development in growing rats J Sci Food Agr 2010 90(9):1485-91.  [Google Scholar]

[59]. Kim E-K, Oh H-J, Kim Y-S, Hwang J-W, Ahn C-B, Lee JS, Purification of a novel peptide derived from Mytilus coruscus and in vitro/in vivo evaluation of its bioactive properties Fish Shellfish Immunol 2013 34(5):1078-84.  [Google Scholar]

[60]. Wallace MS, Charapata SG, Fisher R, Byas-Smith M, Staats PS, Mayo M, Intrathecal ziconotide in the treatment of chronic nonmalignant pain: A randomized, double-blind, placebo-controlled clinical trial Technol Neural Interf 2006 9(2):75-86.  [Google Scholar]